Dataset Information

Characterization of a novel mutation in the MYOC gene in a Chinese family with primary open?angle glaucoma.

ABSTRACT: Although primary open?angle glaucoma (POAG)?related mutations in the myocilin (MYOC) gene have been reported, the underlying associations remain poorly understood. In the present study, the relationship between a MYOC mutation and POAG was investigated using ophthalmic examination and total exon gene sequencing in a Chinese family comprised of 5 individuals with POAG and 15 unaffected individuals. Pathogenic mutations underlying POAG were identified by whole?exome sequencing and subsequently validated by Sanger sequencing. Of the family members, nine (45%) harbored heterozygous p.D208Y mutations; among these, five had POAG and four were unaffected. The mean age at diagnosis was 26.2±4.12 years and the mean intraocular pressure (IOP) was 39.7±16.58 mmHg; all affected members complained of vision loss, headaches and eye swelling. Among the five cases of POAG, two presented with blindness. Among 10 members of the family who underwent comprehensive ophthalmologic examination, 3 individuals exhibited severe visual field defects. The mean age at the time of operation was 27.2±3.54 years. In the present study, a novel MYOC mutation (c.G622T: p.D208Y) was identified that was associated with severe visual impairment, high IOP and the need for frequent surgical interventions. Some carriers of the mutation were young and did not show signs of glaucoma. These individuals should be followed?up to firmly establish whether the mutated gene is pathogenic for POAG.

SUBMITTER: Fan W

PROVIDER: S-EPMC7453629 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Characterization of a novel mutation in the MYOC gene in a Chinese family with primary open‑angle glaucoma.

Fan Wanlin W Li Wan W Duan Chaoye C Zhang Wenbo W Guo Yongwei Y Chen Fei F

Molecular medicine reports 20200819 4

Although primary open‑angle glaucoma (POAG)‑related mutations in the myocilin (MYOC) gene have been reported, the underlying associations remain poorly understood. In the present study, the relationship between a MYOC mutation and POAG was investigated using ophthalmic examination and total exon gene sequencing in a Chinese family comprised of 5 individuals with POAG and 15 unaffected individuals. Pathogenic mutations underlying POAG were identified by whole‑exome sequencing and subsequently val ...[more]

PMID: 32945492

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Project description:PURPOSE: Glaucoma is the leading cause of irreversible blindness worldwide. Most of the cases are primary open angle glaucoma (POAG). POAG is a genetically heterogenous disease; autosomal dominance is the most frequent type of monogenic inheritance. In this study, we identified the genotype of a MYOC mutation and investigated the phenotype of a Chinese juvenile-onset open angle glaucoma (JOAG) pedigree (GZ.1 pedigree). METHODS: Blood samples were obtained from 24 participants. We performed sequence and gene linkage analysis in the GZ.1 pedigree retrospectively. Comprehensive ophthalmologic examinations were performed for each family member. Pharmacological treatment or filtering surgery was performed as needed according to the intraocular pressure (IOP) of each individual. RESULTS: A Pro370Leu myocilin mutation located in exon 3 of MYOC was identified in 24 members of the GZ.1 pedigree. Sixteen patients had juvenile-onset primary open-angle glaucoma (JOAG), and the others participating in the project had no such genotype. Analysis of polymorphic microsatellite markers indicated that the disease in GZ.1 is autosomal dominant inheritance. The patients in GZ.1 are characterized by early age of onset (before 35 years of age), severe clinical presentations, and high intraocular pressure unresponsive to pharmacological treatment; requiring 89.5% of the patients to undergo filtering surgery. Fortunately, the success rate of surgery was high. None of the patients required further medical treatment and only one demonstrated low IOP fundus changes. CONCLUSIONS: This is the first evidence of a founder effect for a Pro370Leu myocilin mutation in a Chinese POAG pedigree. The family with the Pro370Leu myocilin mutation presents with juvenile-onset glaucoma. After 10 years of follow-up, it is evident that the mutation is closely associated with the phenotype of the patients. Analysis of MYOC in JOAG patients may enable the identification of at-risk individuals and help prevent disease progression toward the degeneration of the optic nerve, and may also contribute to genetic counseling.

Project description:AIM:To report the first discovery of Ser341Pro myocilin (MYOC) variant in Korea and analyze its clinical characteristics and genetic significance. METHODS:Ten family members from three generations participated in this study and received the thorough ophthalmologic examination. Focused exome sequencing on a proband was performed to confirm the target mutations (MYOC c.1021T>C) in the family members, and the direct sequencing was conducted. Variant was analyzed according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS:A nucleotide change from thymine to cytosine at c.1021T>C was found in eight family members. Three members diagnosed with primary open angle glaucoma (POAG) were characterized by severe clinical presentations, high intraocular pressure, and poor response to medical treatment (100% of the patient required filtering surgery). On variant analysis by ACMG/AMP guidelines, Ser341Pro is not found in normal population. Multiple computational predictive programs support a deleterious effect of Ser341Pro variant (PolyPhen 2, SIFT, Mutation Taster). Ser341Pro could be involved in moderate (PM) and supporting (PP) criteria (PM1, PM2, PP2, PP3). Combining the criteria, Ser341Pro has a combination of 2 moderate (PM1+PM2) and 2 supporting (PP2+PP3) criteria, which is interpreted to "likely pathogenic". CONCLUSION:The Ser341Pro variant is correlated with severe phenotype of POAG. There are similar clinical aspects to previous studies: autosomal dominant inheritance, incomplete penetrance (62.50% and 66.67%), and proportion of patients requiring trabeculectomy (100% in both study). According to ACMG/AMP guidelines and the previous basic researches, the Ser341Pro variant had a "strong evidence of pathogenicity (PS3)" and then it could be interpreted to "pathogenic (PS3, PM1, PM2, PP2, PP3)". Additionally, Ser341Pro variant can be reported as "c.1021T>C (p.Ser341Pro), likely pathogenic, POAG, autosomal dominant" according to guideline.

Dataset Information

Characterization of a novel mutation in the MYOC gene in a Chinese family with primary open?angle glaucoma.

Publications

Characterization of a novel mutation in the MYOC gene in a Chinese family with primary open‑angle glaucoma.

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